Conformationally constrained aromatic oligoamide foldamers with supersecondary structure motifs

Article abstract of DOI:10.1039/b903178b

The design, synthesis, and structural studies of aromatic foldamers based on oligo(phenanthroline dicarboxamide)s that displayed supersecondary structure motifs have been described. Governed by a combined conformational restriction, the foldamers adopted

Full text of DOI:10.1039/b903178b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Conformationally constrained aromatic oligoamide foldamers with
supersecondary structure motifs†
Hai-Yu Hu,a,b Jun-Feng Xianga and Chuan-Feng Chen*a
Received 16th February 2009, Accepted 6th April 2009
First published as an Advance Article on the web 27th April 2009
DOI: 10.1039/b903178b
The design, synthesis, and structural studies of aromatic foldamers based on oligo(phenanthroline
dicarboxamide)s that displayed supersecondary structure motifs have been described. Governed by a
combined conformational restriction, the foldamers adopted well defined and compact 3D structures,
which have been validated by UV/Vis, NMR spectra, and X-ray crystal analysis. The results presented
here would offer a useful route for the de novo design of aromatic oligoamide foldamers with distinctive
structural architectures.
organized protein-like supersecondary motifs from the assembly of
Introduction
several secondary elements is still an important challenge7 and the
X-ray crystal structures of the supersecondary conformation re-
main even rarer. Therefore, the developments of useful strategies to
control the relative orientation of secondary building blocks within
a tertiary fold play an important role in biological mimicking. In
this paper, we report the design, synthesis, and structural studies
in solution and in the solid state of two new series of aromatic
foldamers based on oligo(phenanthroline dicarboxamide)s that
display helical supersecondary structure motifs.
The mystery of how a protein sequence specifies a unique
structure and function has intrigued chemists’ significant interest
in the design and development of foldamers,1 which are a kind
of synthetic oligomers with definite conformational backbone
structures. Consequently, considerable effort has so far focused on
the creation of unnatural oligomers which are able to mimic many
secondary structural elements of native peptides and proteins, such
as helices,2 sheets,3 and turns.4
A supersecondary structure is the term used to describe certain
common combinations of secondary structure elements that are
observed frequently in protein structures.5 In the hierarchy of
protein structure classification, supersecondary structure falls
between that of secondary structure and tertiary structure, which
can provide a useful way of categorizing distinctive and recurring
components of protein structure.6 However, the design of highly
Recently, we have been studying a new class of aromatic
oligoamides8 based on phenanthroline dicarboxamides, which
exhibited well-defined helical secondary structures in solution and
in the solid state.9 In particular, we reported9b the first artificial aro-
matic oligoamide based helix–turn–helix (HTH) supersecondary
structure, which was composed of two regular helical secondary
structures based on oligo(phenanthroline dicarboxamide) strands
connected with a binaphthyldiamine as the turn. Subsequently,
we deduced that by the insertion of suitable connecting units,
we could obtain new foldamers with specific supersecondary
structures easily. In addition, the rigid aromatic linkers will
improve predictability and stability of the foldamers. Based on our
preceding research, connected with 1,8-diaminoanthraquinone,
the oligo(phenanthroline dicarboxamide)s exhibited well-defined
helical secondary structures under the intramolecular hydrogen
bonds (Fig. 1a). Consequently, we envisioned that changing
aBeijing National Laboratory for Molecular Sciences, CAS Key Laboratory
of Molecular Recognition and Function, Institute of Chemistry, Chinese
Academy of Sciences, Beijing, 100190, China. E-mail: cchen@iccas.ac.cn;
Fax: +86-10-62554449; Tel: +86-10-62588936
bGraduate School, Chinese Academy of Sciences, Beijing, 100049, China
† Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR spectra. TOCSY, NOESY and UV-Vis spectra of 1–6. The X-
ray crystallographic files for 2 and 4. CCDC reference numbers 720731
and 720732. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b903178b
Fig. 1 Schematic representation of the projection of the two helical oligo(phenanthroline dicarboxamide) strands segments in the plane of the
1,8-diaminoanthraquinone spacer (a), 1,4-diaminoanthraquinone spacer (b) and 1,5-diaminoanthraquinone spacer (c). Overlap between the circles
indicates possible steric hindrance between helices if they extend on the same side of the plane of the linkers. The arrows indicate the direction along
which each oligomeric segment extends from the linker.
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the amino position of the diaminoanthraquinone will cause the
conformation of these oligo(phenanthroline dicarboxamide)s to
change from helical structures to supersecondary structures, which
would offer a useful and easy route for the de novo design of
aromatic oligoamide foldamers with distinctive structural archi-
tectures. To confirm this thought, the new oligo(phenanthroline
dicarboxamide)s 1–6 were designed and synthesized, in which
the diaminoanthraquinone subunits not only are used as the
linkers, but also locally set the relative orientation of the secondary
elements. Because rotations about the amide nitrogen-aryl linkages
at the 1 and 4 positions of the anthraquinone would be restricted
structures which will lead to stacking of phenanthroline units.
Consequently, the UV-Vis spectra of the oligomers 1–6 were
recorded in CHCl3. As shown in Fig. 2, the broad band between
300 and 400 nm represents the absorption of the phenanthro-
line unit. It was also found that oligomers 1–3 display absorption
maxima at 343 nm and the values of their corresponding molar
absorptivity were 6.0 ¥ 104, 6.6 ¥ 104, and 9.2 ¥ 104 M-1 cm-1,
respectively. Similarly, the values of the molar absorptivity at
310 nm for oligomers 4–6 were found to be 4.9 ¥ 104, 8.3 ¥ 104, and
9.3 ¥ 104 M-1 cm-1, respectively. As expected, a hypochromic effect
with an increased number of phenanthroline rings was shown,
which implied that helical ordering and p–p* stacking of the
phenanthroline units in oligomers 2, 3, 5, and 6 might exist.
=
by NH ◊ ◊ ◊ O C hydrogen bonds, steric hindrance was expected to
prevent the two helical segments from extending on the opposite
side of the linker, and the helices should be both right-handed
(P-P) or both left-handed (M-M) (Fig. 1b). A similar case could
also be applied in the helical supersecondary structures with 1,5-
diaminoanthraquinone as the linker, in which steric hindrance
would result in the two helical segments in opposite handedness
(P-M) (Fig. 1c).
Results and discussion
Synthesis
As shown in Scheme 1, the oligomers 1–6 were synthesized
in high yields by the reaction of the appropriate monoacid8a
with 1,4-diaminoanthraquinone or 1,5-diaminoanthraquinone in
CH2Cl2 in the presence of dicyclohexylcarbodiimide (DCC) and 1-
hydroxybenzotriazole (HOBt). All products have been purified by
column chromatography or crystallization, and characterized by
1H NMR, 13C NMR, MALDI-TOF MS spectra, and elementary
analyses.
Fig. 2 UV-Vis spectra of the molecular strands 1–6 in CHCl3 (c = 2 ¥
10-5 M).
NMR analysis
UV-Vis analysis
For further investigation of the solution-state conformation, we
performed detailed NMR studies of the oligomers in CDCl3
solution. With the additional TOCSY NMR data, the peaks of
We first examined the intramolecular interactions of the oligomers
through the absorption spectra for the formation of helical
Scheme 1 Synthetic schemes of compounds 1–6.
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the aromatic protons and amide protons in 1 and 2 were assigned
(see ESI†). Two-dimensional NOESY H NMR spectroscopy in
restrictions. The two helical segments are found on opposite sides
of the anthraquinone. If the two helices were located on the
same side, they would bump into each other. Fig. 4b shows the
two helices having the same handedness with a complete turn
(M-M); however, the crystal is racemic with both P-P and M-
M handed forms present in the unit cell (Fig. 4c), and there
is an intermolecular face-to-face p–p stacking between the two
phenanthroline rings of the adjacent foldamers with a distance
1
CDCl3 revealed the presence of close contacts between proton Hj
in the anthraquinone ring and Hb in the benzene ring of 1, which
indicated that the rigid linker, 1,4-diaminoanthraquinone, locally
set the relative orientation of the phenanthroline units (Fig. 3b).
Additionally, the NOESY spectrum of oligomer 2 also revealed
cross-peaks supporting a helical conformational preference in
CDCl3. For example, amide proton Hn, located on the interior ring,
exhibited cross-peaks with the amide proton (Hl) and protons (Hi,
Hj) on the anthraquinone ring located in regions above its position
in the helix of 2 (Fig. 3c, d).
˚
of 3.41 A. In the case of oligomer 4, its crystal structure also
shows (Fig. 4d, e) a clear supersecondary structure stabilized by a
network of intramolecular hydrogen bonds. As expected, the rigid
linker 1,5-diaminoanthraquinone sets the relative orientation of
the two helical structures, and the two helical segments of oligomer
4 were also found on opposite sides of the linker. Compared
with oligomer 2, the structure of oligomer 4 possessed a center
of symmetry in the middle of the anthraquinone ring. Thus,
the two helices have opposite handedness, giving rise to meso-
helicity.10 Only one conformation (M-P) was presented in the unit
cell (Fig. 4f), and there is also an intermolecular face-to-face p–
p stacking between the two phenanthroline rings of the adjacent
X-Ray crystal analysis
The concept was directly validated in the solid state by the single-
crystal structures of oligomers 2 and 4. The single crystal of
oligomer 2 was obtained from a mixture of CH2Cl2, CH3OH and
CH3CH2OH after slow solvent evaporation at room temperature.
As shown in Fig. 4a, the oligomer 2 consists of two regular helices
linked by the rigid 1,4-diaminoanthraquinone, which formed a
supersecondary structure. Rotations around the aryl–NH bonds
of the linker are expectedly restricted by a strong intramolecular
hydrogen bond between the anthraquinone oxygens and the
˚
foldamers with a distance of 3.34 A.
Conclusions
˚
=
neighboring amide protons with the C O ◊ ◊ ◊ N distance of 2.62 A;
In summary, we have presented two series of artificial aro-
matic oligoamide based supersecondary structures, which were
the entire structure was held by the network of conformational
Fig. 3 (a) Molecular structures of 1 and 2 with selectively numbered protons. Partial 2D NOESY spectra (5 mM, 600 MHz, CDCl3, 298 K) of (b) 1,
and (c), (d) 2 showing characteristic nOe.
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Fig. 4 Crystal structures of 2 (a) top view, (b) side view and (c) crystal packing (along an axis) with methanol molecules presented at the ends of the
helix, and 4 (d) top view, (e) side view and (f) crystal packing (along an axis). Isobutyl chains and hydrogen atoms are omitted for clarity.
composed of two canonical helical secondary structures based
on oligo(phenanthroline dicarboxamide) strands and diaminoan-
thraquinones inserted as the linkers. The very well defined su-
persecondary structures have been demonstrated by the UV/Vis,
NMR spectra, and X-ray crystal analysis. Conformational in-
vestigations suggested that the aromatic linkers and their steric
hindrance could control the relative orientation and handedness
of two folded helical oligomers easily. The results presented here
would offer a useful route for the de novo design of aromatic
oligoamide foldamers with distinctive structural architectures.
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Future work will be focused on the new highly organized artificial
structures based on the oligo(phenanthroline dicarboxamide)
helical foldamers, and their potential applications in asymmetric
catalysis and materials science.
121.6, 120.8, 120.4, 120.3, 120.2, 120.1, 102.2, 101.6, 101.4, 101.3,
101.2, 101.1, 101.0, 100.89, 100.85, 100.8, 100.7, 100.6, 100.5, 75.5,
75.4, 75.1, 75.0, 74.8, 74.7, 28.6, 28.5, 28.3, 28.2, 28.1, 19.8, 19.5,
19.4, 19.3, 19.0, 18.9. MALDI TOF MS: m/z 3116 [M + H]+.
Anal. Calcd. for C182H176N24O26·2H2O: C, 69.36; H, 5.76; N, 10.67.
Found: C, 69.40; H, 5.76; N, 10.59%.
Experimental
◦
1
Compound 4. Yield: 98%. Mp >300 C. H NMR (CDCl3,
600 MHz): 14.60 (s, 2H, NH), 11.37 (bs, 2H, NH), 9.17 (s, 2H, J =
8.3 Hz), 8.42–8.38 (m, 4H), 8.11 (s, 2H), 7.73–7.69 (m, 6H), 7.30
(t, 2H, J = 7.9 Hz), 7.02 (bs, 4H), 6.81 bs, 2H), 4.32–4.22 (m, 8H,
-OCH2CH(CH3)2), 2.43–2.36 (m, 4H, -OCH2CH(CH3)2), 1.24–
1.22 (m, -OCH2CH(CH3)2, 24H). 13C NMR (CDCl3, 150 MHz):
187.7, 164.6, 163.5, 151.3, 140.4, 137.5, 135.5, 134.6, 128.3, 126.2,
124.6, 123.8, 123.2, 123.0, 121.5, 121.0, 120.7, 118.1, 102.2, 96.1,
75.6, 28.3, 19.3. MALDI TOF MS: m/z 1200 [M + Na]+. Anal.
Calcd. for C70H64N8O10·H2O: C, 70.34; H, 5.57; N, 9.37. Found:
C, 70.44; H, 5.59; N, 9.48%.
General method for the synthesis of oligomers 1–6
To a solution of the diaminoanthraquinone 10 or 11 (1.19 g,
0.5 mmol) in CH2Cl2 (50 mL) was added the corresponding acid
(1.5 mmol), 1-hydroxylbenzotriazole (HOBt) (230 mg, 1.5 mmol),
and DCC (309 mg, 1.5 mmol). The reaction mixture was stirred at
room temperature, and then refluxed for about 2 weeks. The pre-
cipitates were removed by filtration through Celite. The solution
was concentrated, and the residue was washed with MeOH. The
solid was purified by silica-gel column chromatography (ethyl
acetate–dichloromethane–petrol ether 1 : 2 : 3) to give the product
as an orange solid.
◦
1
Compound 5. Yield: 96%. Mp >300 C. H NMR (CDCl3,
600 MHz): 13.38 (bs, 2H, NH), 11.60 (s, 2H, NH), 11.39 (bs,
2H, NH), 11.00 (bs, 2H, NH), 9.02 (bs, 2H), 8.33 (d, 2H, J =
9.0 Hz), 8.24 (bs, 4H), 8.18 (d, J = 9.0 Hz, 2H), 7.79–7.50 (m,
20H), 7.20 (bs, 4H), 7.31 (bs, 2H), 7.05 (bs, 4H), 6.96 (t, 2H,
J = 7.3 Hz), 4.24–4.36 (m, 16H, -OCH2CH(CH3)2), 2.40–2.16 (m,
8H, -OCH2CH(CH3)2), 1.23–1.09 (m, -OCH2CH(CH3)2, 48H).
13C NMR (CDCl3, 150 MHz): 164.0, 163.6, 163.3, 163.2, 162.8,
162.7, 151.4, 151.3, 150.4, 145.43, 145.35, 145.25, 145.18, 145.13,
145.09, 140.2, 138.0, 134.6, 130.2, 128.9, 126.12, 126.09, 125.2,
124.3, 124.2, 123.4, 122.9, 122.52, 122.47, 122.42, 122.40, 121.05,
121.02, 120.99, 120.44, 120.40, 120.33, 120.31, 120.2, 118.3, 102.3,
101.7, 101.63, 101.60, 75.6, 75.4, 74.8, 28.5, 28.42, 28.39, 19.49,
19.45. MALDI TOF MS: m/z 2169 [M + Na]+. Anal. Calcd. for
C126H120N16O18: C, 70.51; H, 5.64; N, 10.44. Found: C, 70.42; H,
5.72; N, 10.38%.
◦
1
Compound 1. Yield: 91%. Mp >300 C. H NMR (CDCl3,
600 MHz): 14.21 (s, 2H, NH), 10.50 (bs, 2H, NH), 9.60 (s, 2H),
8.41–8.37 (m, 4H), 8.23 (bs, 2H), 8.12 (s, 2H), 7.66–7.60 (m, 6H),
6.94–6.93 (m, 4H), 6.84 (bs, 4H), 6.62 (bs, 2H), 4.27–4.21 (m, 8H,
-OCH2CH(CH3)2), 2.42–2.35 (m, 4H, -CH2CH(CH3)2), 1.22–1.21
(m, -CH2CH(CH3)2, 24H). 13C NMR (CDCl3, 150 MHz): 188.1,
165.0, 163.5, 151.7, 151.4, 145.7, 138.1, 137.7, 133.5, 132.4, 129.7,
128.4, 127.0, 124.4, 123.2, 123.0, 120.9, 120.7, 119.8, 102.3, 75.7,
28.4, 19.5. MALDI TOF MS: m/z 1178 [M + H]+. Anal. Calcd.
for C70H64N8O10: C, 71.41; H, 5.48; N, 9.52. Found: C, 71.22; H,
5.57; N, 9.36%.
Compound 2. Yield: 93%. Mp 296–298 ◦C. 1H NMR (CDCl3,
600 MHz): 14.09 (s, 2H, NH), 11.61 (s, 2H, NH), 11.36 (s, 2H,
NH), 11.61 (bs, 2H, NH), 9.36 (s, 2H), 8.38 (d, 2H, J = 9.1 Hz),
8.26–8.24 (m, 4H), 8.15 (d, J = 9.1 Hz, 2H), 8.06 (bs, 2H), 7.77–
7.52 (m, 16H), 7.31 (bs, 2H), 7.20 (bs, 4H), 7.06 (t, 2H, J = 6.7 Hz),
6.98–6.91 (m, 4H), 4.15–4.02 (m, 12H, -OCH2CH(CH3)2), 3.54
(bs, 4H, -OCH2CH(CH3)2), 2.40–2.17 (m, 8H, -OCH2CH(CH3)2),
1.23–1.11 (m, -OCH2CH(CH3)2, 48H).13C NMR (CDCl3,
150 MHz): 188.1, 164.1, 163.5, 163.3, 163.2, 162.7, 162.6, 161.9,
151.4, 151.3, 150.6, 150.2, 145.4, 145.3, 145.2, 145.0, 137.9, 137.5,
134.3, 132.2, 130.3, 129.0, 128.3, 126.5, 125.8, 124.1, 123.0, 122.8,
122.4, 121.1, 120.2, 119.8, 102.3, 101.6, 75.6, 75.5, 75.4, 74.7,
39.1, 38.9, 34.3, 32.9, 32.0, 29.8, 29.6, 29.4, 29.2, 28.5, 28.4,
28.1, 23.1, 22.85, 22.82, 20.3, 19.5, 19.4, 19.3, 14.6, 14.33, 14.28,
11.6. MALDI TOF MS: m/z 2169 [M + Na]+. Anal. Calcd. for
C126H120N16O18·2H2O: C, 69.34; H, 5.73; N, 10.27. Found: C, 69.56;
H, 5.93; N, 9.85%.
◦
1
Compound 6. Yield: 89%. Mp >300 C. H NMR (CDCl3,
600 MHz): 13.06 (bs, 2H, NH), 11.04–9.76 (m, 10H, NH), 8.30–
6.49 (m, 56H), 4.05–3.61 (m, 24H, -OCH2CH(CH3)2), 2.35–2.06
(m, 12H, -OCH2CH(CH3)2), 1.25–1.00 (m, -OCH2CH(CH3)2,
72H). 13C NMR (CDCl3, 150 MHz): 164.1, 164.0, 163.8, 163.6,
163.5, 163.4, 163.42, 163.35, 163.2, 163.0, 162.7, 162.5, 162.4,
162.3, 162.2, 162.04, 161.98, 161.91, 161.87, 161.7, 161.43, 161.36,
161.3, 151.7, 151.5, 151.4, 151.3, 150.9, 150.8, 150.7, 150.6, 150.5,
150.43, 150.39, 150.3, 150.2, 150.2, 150.1, 150.0, 149.9, 149.8,
149.6, 149.5, 149.44, 149.38, 145.36, 145.3, 145.0, 144.8, 144.4,
139.4, 139.35, 139.30, 138.1, 134.0, 133.8, 133.6, 130.7, 128.8,
125.6, 124.0, 123.2, 122.8, 122.5, 122.3, 122.1, 121.3, 120.8, 120.4,
120.3, 120.1, 119.8, 119.7, 119.6, 117.85, 117.79, 102.1, 101.82,
101.76, 101.7, 101.6, 101.4, 101.32, 101.26, 101.1, 101.0, 100.9,
100.8, 100.7, 100.6, 100.5, 100.4, 100.3, 100.24, 100.20, 100.1,
75.5, 75.0, 29.9, 28.4, 28.3, 28.1, 27.9, 19.8, 19.5, 19.4, 19.3,
18.8. MALDI TOF MS: m/z 3138 [M + Na]+. Anal. Calcd. For
C182H176N24O26·H2O: C, 69.76; H, 5.73; N, 10.73. Found: C, 69.63;
H, 5.84; N, 10.62%.
◦
1
Compound 3. Yield: 84%. Mp >300 C. H NMR (CDCl3,
600 MHz): 13.56 (bs, 2H, NH), 11.14–10.11 (m, 10H, NH),
8.83–6.19 (m, 56H), 4.03–3.61 (m, 24H, -OCH2CH(CH3)2), 2.33–
1.96 (m, 12H, -OCH2CH(CH3)2), 1.25–0.87 (m, -OCH2CH(CH3)2,
72H). 13C NMR (CDCl3, 150 MHz): 163.4, 163.3, 163.0, 162.9,
162.8, 162.7, 162.5, 162.3, 162.2, 162.10, 162.06, 162.0, 161.9,
161.8, 161.70, 161.66, 161.6, 161.5, 160.7, 151.1, 151.0, 150.9,
150.3, 150.2, 150.1, 150.0, 149.94, 149.89, 149.82, 149.7, 149.6,
145.3, 145.2, 145.1, 145.10, 145.05, 144.8, 144.5, 138.0, 137.1,
131.4, 130.3, 128.9, 128.6, 126.2, 125.8, 125.3, 125.2, 124.5, 124.4,
124.3, 124.0, 123.3, 123.1, 122.8, 122.3, 122.2, 122.10, 122.05,
Acknowledgements
We thank the National Natural Science Foundation of China
(20625206), CMS-CX200826, and National Basic Research
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Program of China (2007CB808004, 2008CB617501) for financial
support. We also thank Dr Hai-Bin Song at Nankai University
for determining the crystal structures.
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